Multiparticulate L-Menthol Formulations and Related Methods

ABSTRACT

A pharmaceutical dosage form includes an effective amount of L-menthol for treating a gastrointestinal disorder. The L-menthol is within a plurality of particulates having a core including crystalline L-menthol dissolved in a terpene-based essential oil. A proteinaceous coating of a continuous film of proteinaceous material is over the core.

CROSS-REFERENCE TO RELATED APPLICATIONS

This is a divisional of U.S. application Ser. No. 14/971,009, filed Dec.16, 2015, which is a continuation of U.S. application Ser. No.14/535,598, filed Nov. 7, 2014, which is a continuation of U.S.application Ser. No. 14/033,737, filed Sep. 23, 2013, which claimspriority to U.S. provisional Application No. 61/815,073, filed Apr. 23,2013 and U.S. provisional Application No. 61/880,294, filed Sep. 20,2013, and which is a continuation-in-part of U.S. application Ser. No.13/367,747, filed Feb. 7, 2012, which claims priority to U.S.provisional Application No. 61/441,716, filed Feb. 11, 2011, and U.S.provisional Application No. 61/486,523, filed May 16, 2011. Each ofthese prior applications is incorporated by reference herein in itsentirety.

FIELD

This relates to multiparticulate formulations for delivering L-mentholto the intestines, and, more particularly, to enteric coated L-mentholmultiparticulate formulations and related methods.

BACKGROUND

Essential oils have been used for their bioactivity for quite some time.Some essential oils are currently being used as medicaments. For examplethe plants mentha piperita or mentha arvensis, are the two primarysources of peppermint oil. Peppermint oil is effective at treating thesymptoms of gastrointestinal disorders such as irritable bowel syndrome(IBS), functional dyspepsia (FD), gastro paresis (GP), Crohn's disease(CD) and ulcerative colitis (UC). These symptoms can include pain,discomfort, bloating, constipation, and/or diarrhea. Clinical trialshave demonstrated significant alleviation of the symptoms associatedwith IBS through the use of peppermint oil in single-unit capsulescoated with the cellulose acetate-phthalate enteric polymer or otherenteric-coating polymers.

For maximal efficacy in the treatment of IBS, FD, GP, CD and UC, and toavoid related complications, peppermint oil should be locally deliveredto various sections of the intestines (i.e. duodenum, small intestine,ileum or large intestine [i.e. colon]), while avoiding the stomach. Ifpeppermint oil is released from its dosage form prior to passing throughthe pyloric sphincter into the intestines, it can irritate the mucousmembranes in the upper digestive tract. Releasing peppermint oildirectly into the stomach can cause heartburn (gastric irritation) andgastro-esophogeal reflux disease. Therefore, since peppermint oil isusually administered orally, it should preferably be prepared with anenteric coating.

Enteric-coated single-unit capsules for treating irritable bowelsyndrome and functional dyspepsia that contain peppermint oil currentlyexist. But, even though the enteric coated single-unit capsules aremeant to delay the release of peppermint oil until after the capsuleenters the intestines, this approach to treating gastrointestinal (GI)disorders has several drawbacks. The drawbacks include premature releaseof the peppermint oil from the capsule in the stomach, resulting inheartburn. Also, accidental chewing of the capsule causes the entericcoat to rupture prematurely and release the oil in the stomach.

The oil that is released from single-unit capsules is typicallydissolved in cooking oil (such as peanut oil) to modify its release inthe intestines. The peppermint oil (dissolved in cooking oil) releasedfrom single unit capsules, does not dissolve in the aqueous contents ofthe stomach but forms a layer of oil which floats on top of the aqueousphase in the stomach. This increase the likelihood of the peppermint oilplus cooking oil regurgitating into the esophageal area and causingreflux.

Using current formulations of peppermint oil, significant doses arerequired to achieve an efficacious concentration of peppermint oil inthe body. For example, each of the above referenced capsules containsabout 200 mg of peppermint oil and must be taken three times a day,30-60 minutes prior to a meal. The dose can be increased to two capsulestaken three times daily in some situations.

Enteric-coated peppermint oil is typically administered as a single-unitcapsule formulation. However, in a single-unit formulation, the amountof peppermint oil absorbed by the intestines can vary from dose to dosefor several reasons. First, single-unit enteric capsule formulation canget attached to the esophagus because of the muco-adhesive properties ofthe enteric coat and, therefore, not enter the stomach within thedesired time frame. The single-unit enteric coated capsules, likeenteric coated single-unit tablets, have been shown to not release theactive ingredient from the single-unit formulation because thesingle-unit's size is too large to pass through the constriction in thestomach's pylorus valve, until the inter-digestive or house cleaningphase. The enteric coat of the capsule may also prematurely crack orrupture because of the force created by the swelling of the gelatin orhypromellose used to form the capsule shell due to its water ofhydration, against the outer enteric coat. Because peppermint oilcontaining capsules have a lower specific gravity than the stomachcontents, they tend to float rather than settle and pass through thepylorus constriction between the stomach and the lower intestines,unreliably and only during the inter-digestive phase.

Non-disintegrating tablets or capsules given with food may stay in thestomach for long times, up to 10 to 15 hours, before they are emptiedinto the small intestine. Small particles, with diameters less than orabout 3 mm, are emptied from the stomach more regularly, regardless ofwhether they are given with food. The 10 to 15 hours that an entericcoated hard gelatin or hypromellose capsule may get exposure to gastricconditions in a fed state may cause the enteric coat to rupture and thehard gelatin (or hypromellose) seal coat to dissolve, resulting in thepeppermint oil being released in the stomach and causing heartburn orgastric irritation.

Even if the single-unit enteric coated capsule passes through thepylorus intact in a timely fashion, when it reaches the small intestine,the coating dissolves and a bolus of oil is released. This dosagedumping is a situation in which the active ingredient is released andgives very high local exposure in a segment of the intestine, is alsoundesirable because it prevents uniform and steady exposure ofpeppermint oil in the GI lumen. This high local exposure to one sectionof the GI lumen may actually aggravate symptoms of IBS.

Single-unit formulations are also significantly influenced by thepresence of food in the stomach. Gastric emptying rates of single-unitdoses are erratic and unpredictable. Single-unit enteric-coated tabletsor capsules taken with food may stay in the stomach for many hoursbefore being emptied into the small intestine. As a result, single-unitformulations present both high inter and intra-subject variability withrespect to the pharmacokinetics (PK) and local bioavailableconcentration of active ingredient. According to regulatory guidelines,enteric-coated single-unit capsules can never be bioequivalent withmultiple-unit enteric-coated dosage forms. A single-unit entericpreparation containing peppermint oil was disclosed in U.S. Pat. No.4,687,667.

The currently available delayed release single-unit dosage formscontaining enteric-coated peppermint oil have another limitation. Theydump their primary active ingredient, L-menthol, when the enteric layerdisintegrates. The terminal half-life of L-menthol is −1.34 hours.Therefore, the systemic exposure of L-menthol is limited toapproximately 4 hours, resulting in the need for frequent dosing(usually three times a day) to relieve the symptoms of IBS. Thepeppermint oil is usually dissolved in cooking oil to slow the releaseof L-menthol into the aqueous phase. However, cooking oil can aggravatethe symptoms of IBS and the rate of release from the cooking oil isdependent on the diameter of the droplets of the oil. The diameter ofthe oil droplets is controlled by the presence of surfactants (bileacids etc.) and other oily substances in the stomach. With amultiparticulate delivery system, the individual particles pass throughthe pylorus over a longer period (approximately 90 minutes) and releasetheir content steadily over this time period. The use of a single-unitnon-disintegrating delayed release dosage form is undesirable becausethey release (dump) their active ingredient immediately after the singleunit's enteric layer is dissolved.

In U.S. patent publication 2012/0207842, we described enteric coatedmultiparticulate L-menthol compositions adapted to overcome thedrawbacks associated single-unit dosage forms. In order to prevent theL-menthol from sublimating as the cores were being processed, weresorted to low temperature processing techniques. The L-mentholmultiparticulate compositions described in that application provided therelease profile that we desired and worked well for some applications,but were not optimized for all applications.

We have identified a need for a multiparticulate L-menthol-containingformulation that avoids the drawbacks associated with single-unitenteric coated capsules and can be made using conventional roomtemperature processing techniques

SUMMARY

An aspect of the invention is to provide an L-menthol multiparticulateformulation with an enteric coating, using high-purity L-menthol. Such aformulation comprises a plurality of individual enteric coated corescontaining L-menthol from an at least 80% pure L-menthol source, theenteric coated cores being effective to release at least about 35% ofthe L-menthol within about two hours, and at least about 80% of theL-menthol within about eight hours after being placed in an environmenthaving a pH of between 5 to 8.

The enteric coated cores may further comprise a proton pump inhibitor,green tea extract, anti-inflammatory, and/or immune suppressor.

A continuous proteinaceous subcoating layer may cover the individualcores and separate the individual cores from their respective entericcoatings. A preferred proteinaceous subcoating comprises a gelatin filmadhered to the core. The continuous proteinaceous subcoating maycomprises a dried proteinaceous gel. The continuous proteinaceoussubcoating is adapted to prevent the L-menthol from mixing with theenteric coating or forming L-menthol whiskers in the dosage form duringstorage.

The enteric coating may have a glass transition temperature higher thana standard boiling point of the peppermint oil.

The L-menthol may be dissolved in a solubilizing oil, which may containone or more terpenes such as caraway oil and peppermint oil.

The enteric coated cores may further comprise an antioxidant effectivefor preventing L-menthol oxidation.

In a preferred embodiment, the enteric coated cores comprise about 10%w/w to about 70% w/w L-menthol.

The enteric coated cores may further comprise epigallocatechin gallate(EGCG) or a green tea extract with a high EGCG content.

In a preferred embodiment of the multiparticulate composition, the corescomprise about 10% w/w to about 35% w/w L-menthol, about 40% w/w toabout 75% w/w microcrystalline cellulose, about 2% w/w to about 10% w/wmethyl cellulose, and about 0.05% w/w to about 20% w/w of croscarmellosesodium; the subcoating comprises about 3.5% w/w to about 35% w/w of theuncoated cores; and the enteric coating comprises about 2% to about 35%w/w of the uncoated cores.

In a first method aspect of the invention, a method of making amultiparticulate formulation comprises blending L-menthol from an atleast 80% pure L-menthol source, microcrystalline cellulose, ahydrophilic binder, and water to form a wet mass; extruding the wet massto form an extrudate; dividing the extrudate into individual wet cores;drying the wet cores to form dried cores; and applying a subcoatfollowed by an enteric coating to the dried cores.

The hydrophilic binder may be selected from cellulose-based binder,starch based binder, povidone based binder, or a combination thereof.

A particularly preferred hydrophilic binder is methyl cellulose.

The method may further comprise coating the dried cores with a liquidproteinaceous material and drying the liquid proteinaceous material toform sub-coated cores prior to applying the enteric coating. The liquidproteinaceous material may comprises gelatin, such as a solutioncontaining at least about 35% gelatin.

Coating the dried cores with a liquid proteinaceous material maycomprise spraying the liquid proteinaceous material onto the driedcores.

The enteric coated cores are preferably spheroidal and not more than 3mm in diameter.

The wet mass may further comprise caraway oil, peppermint oil, a PPI, ananti-inflammatory (such as the 5-ASA class), an immune suppressor (suchas corticosteroids), or a green tea extract enriched in epigallocatechingallate. In a second method aspect of the invention, a method oftreating a gastrointestinal disorder in a subject comprisesadministering to the subject a multiparticulate formulation comprising aplurality of individual enteric coated cores containing L-menthol froman at least 80% pure L-menthol source, the enteric coated cores beingeffective to release at least about 35% of the L-menthol within abouttwo hours, and at least about 80% of the L-menthol within about eighthours after being placed in an environment having a pH of 5 to 8.

Administering may be performed enterally.

The multiparticulate formulation may be blended with an acidic vehicleprior to being administered.

The L-menthol in the enteric coated cores may be dissolved in carawayoil, with or without a proton pump inhibitor, which is particularlyuseful to treat functional dyspepsia and/or gastroparesis.

The L-menthol in the enteric coated cores may be dissolved in peppermintoil, which is particularly useful to treat irritable bowel syndrome.

When the gastrointestinal disorder treated is inflammatory boweldisease, it may be beneficial if the enteric coated cores furthercontain one or more of epigallocatechin gallate (or green tea extractcontaining EGCG), an aminosalicylate, or a corticosteroid.

These and other objects, aspects, and advantages of the presentinvention will be better appreciated in view of the drawings andfollowing description of certain embodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a graph showing the results of an accelerated stability assayfor a multiparticulate formulation according to an embodiment of theinvention stored at 40 degrees C. and 75% relative humidity for fourweeks; and

FIG. 2 is a graph showing the results of a two-stage dissolution testfor a multiparticulate formulation according to an embodiment of theinvention after the composition was stored at 40 degrees C. and 75%relative humidity.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

The Summary, Detailed Description of Preferred Embodiments, and thedrawings refer to particular features (including method steps) of theinvention. The disclosure of the invention in this specificationincludes all possible combinations of such particular features. Forexample, where a particular feature is disclosed in the context of aparticular aspect or embodiment of the invention, that feature can alsobe used, to the extent possible, in combination with and/or in thecontext of other particular aspects and embodiments of the invention,and in the invention generally.

The term “comprises” is used herein to mean that other ingredients,steps, etc. are optionally present. When reference is made herein to amethod comprising two or more defined steps, the steps can be carried inany order or simultaneously (except where the context excludes thatpossibility), and the method can include one or more steps which arecarried out before any of the defined steps, between two of the definedsteps, or after all of the defined steps (except where the contextexcludes that possibility).

In this section, the invention will be described more fully withreference to certain preferred embodiments. This invention may, however,be embodied in many different forms and should not be construed aslimited to the embodiments set forth herein.

Because L-menthol is volatile, it is difficult to makeL-menthol-containing dosage forms. Typical processing methods for makingpharmaceutical dosage forms involve heating, which conventional wisdomsuggests one should avoid when using volatile ingredients. We found thatit is very difficult to make stable multiparticulate L-mentholcontaining compositions for this and other reasons. The volatile natureof L-menthol, along with its relatively unique property of formingwhiskers on the surface of multiparticulates when the formulations arestored at above room temperature, poses a special challenge for entericcoated multiparticulates. The L-menthol whiskers that form on thesurface of the enteric coated multiparticulate (within the capsule orsachet/stick type dosage forms) can result in appearance failures anddissolution failures under acid conditions.

As with peppermint oil, smooth muscle contractions in thegastrointestinal tract can be inhibited using L-menthol, the mainbioactive component in peppermint oil. Peppermint oil derived fromMentha piperita only contains up to 50% menthol and Mentha arvensiscontains only approximately 70-80% menthol. The other components ofpeppermint oil include menthone, pulegone, menthofuran, cineole, methylacetate and limonene. There is significant variation in the relativecomposition of these other components based on the phenotype of theplant, geographic production area and harvest time. Also, some of thesecomponents may not be active thereby result in needing higher doses ofpeppermint oil versus doses of L-menthol, to get the same activity. Incontrast to peppermint oil, which is primarily available as a liquid,L-menthol is available in liquid and crystalline powder forms. We haveadvantageously developed a unique combination of ingredients andprocessing methods for providing an enteric coated multiparticulateformulation comprising L-menthol from an at least 80% pure L-mentholsource.

The multiparticulate formulation aspect of the invention is firstdescribed. The multiparticulate formulation is adapted to carryL-menthol to the intestines and includes a plurality of particulatesthat are preferably spheroidal in shape and are sized to fit through thepyloric sphincter when it is in a relaxed state. The diameter of eachparticulate is preferably in the range of about 0.1 mm to about 3 mm or,about 1 mm to about 2.5 mm, or less than about 1.4 mm. Particulates ofthis diameter are advantageous because they can fit through the pyloricsphincter and do not remain in the stomach as long as single-unitcapsules, thereby providing a more reliable onset of action.

The multiparticulate composition includes a plurality of individualL-menthol containing cores that are each enteric coated. The entericcoating allows the individual cores to pass through the stomach withoutreleasing a substantial amount of L-menthol. In the pH of theintestines, the enteric coating dissolves, exposing the cores andallowing oil-menthol to be released.

The core contains the primary active ingredient L-menthol, but may alsocontain other secondary active ingredients such as one or more otherterpene-based substances such as terpenes, terpenoids, and/or essentialoils. Terpene-based substances that may be used as secondary activeingredients include but are not limited to peppermint oil, caraway oil,orange oil, ginger oil, turmeric oil, curcumin oil, and fennel oil,among others. These terpenes are also solubilizing agents for L-menthol.The L-menthol solubilized in other terpenes reduces the tendency ofL-menthol to form whiskers.

In the crystalline form, L-menthol is substantially free of impuritiesand has a consistent composition. Although it may not always benecessary, it is preferred that the starting material for L-mentholappear as visually perceptible L-menthol crystals. A preferredconcentration of L-menthol in the core is between about 10% to about 70%w/w.

Alternatively, the secondary active ingredient may be anon-terpene-based substance that helps relieve gastrointestinal disordersymptoms from their various actions. Examples of non-terpene secondaryactive ingredients include, but are not limited to, polyphenols such asgreen tea extracts and aloe vera powder among others. The primary activeingredient in green tea extract is epigallocatechin gallate.

Because L-menthol is not very soluble in water, it may be advantageousto include a solubilizing agent. Preferred solubilizing agents includeoils, such as essential oils. Essential oils are particularlyadvantageous for two main reasons. First, L-menthol readily dissolves inessential oils. Second, some essential oils are synergisticallyeffective to treat symptoms of certain gastrointestinal disorders.

Essential oils such as peppermint oil, caraway oil, orange oil, fenneloil, etc. are liquid at room temperature. They are usually formulated asliquids in a capsule, with an enteric-coating over the capsule. Wediscovered that essential oils can be mixed with a cellulosic filler anda binder to make a dough or wet mass, but the dough formed by simplymixing these materials together does not produce a core with the desiredstrength for subcoating and further processing. By adding water to thewet mass, we produced cores containing an essential oil that were robustenough for subsequent processing.

The core may also contain one or more antioxidants that can maintain thepurity of the L-menthol and other active ingredients if used. This isuseful because L-menthol can oxidize to form undesirable derivatives.Examples of antioxidants that may be used include, but are not limitedto tocopherol (vitamin E) BHT (butylated hydroxy toluene), BHA(butylayted hydroxy anisole), and ascorbic acid.

Microcrystalline cellulose, or “MCC,” is a pharmaceutical excipient thatis widely used as a disintegrant in solid oral dosage forms. MCCpromotes the breakup of tablets in aqueous environments to enhance drugrelease. It does this by wicking moisture through the pores of thetablet, weakening the tablet and causing it to disintegrate. Since MCCis used as a disintegrant, its causes the active ingredients in thesolid oral dosage form to be released faster than they would otherwisebe released.

We found that MCC also functions as a release-controlling polymer forL-menthol and essential oils. Accordingly, the core may include MCC.This is especially useful when L-menthol is blended with an oil such asan essential oil, including peppermint oil and/or caraway oil. The MCCis effective to gradually release the L-menthol into the intestinesrather than quickly dumping the entire dose in a small region of theintestines. Accordingly, the MCC in our multiparticulate L-mentholcompositions performs the opposite function of a disintegrant andovercomes the dose-dumping drawback held by the conventional single-unitenteric coated capsules. The blending of the L-menthol with caraway orpeppermint oil also reduces the likelihood of forming L-mentholwhiskers, which can lead to appearance and dissolution failures.

In such an embodiment, L-menthol is dissolved in the essential oil andis then combined with MCC and a hydrophilic binder such as acellulose-based, starch-based, and/or povidone-based binder. It is to beunderstood that “cellulose-based,” “starch-based” binders, and“povidone-based” binders includes cellulose, starch, and povidonederivatives. When mixed with water, the hydrophilic binder swells toform a hydrogel matrix. In contrast, MCC, L-menthol, and the oil arehydrophobic.

Examples of cellulose-based binders include methylcellulose basedpolymers, including, for example, methylcellulose and hydroxypropylmethylcellulose. Methylcellulose is particularly preferred for use inthe composition.

When water is added to the core during processing, these materialsseparate into a hydrophobic phase and hydrophilic phase. The hydrophobicphase contains L-menthol and the oil dispersed in the microcrystallinecellulose based gel and the hydrophilic phase contains the hydrophilicbinder. The L-menthol dissolved in the oil is dispersed throughout thehydrophobic phase.

One of the advantages of dispersing the solubilized L-menthol in MCC isthat it allows excess water to be removed from the cores without alsoremoving a substantial amount of the L-menthol. Conventional dryingtechniques would cause the L-menthol and oil in the core to evaporatewith the water. Thus, by making the core to include a hydrophobic phasecontaining L-menthol dispersed in a microcrystalline cellulose-based geland a hydrophilic phase containing a hydrophilic binder, the core can beprocessed without risking substantial loss of the L-menthol.

The core may also include pharmaceutically acceptable fillers,stabilizers, binders, surfactants, processing aids, and/ordisintegrants. By way of example only, suitable materials for performingthese functions are provided.

Preferred fillers include cellulosic filler materials such asmicrocrystalline cellulose, dibasic calcium phosphate, and/or anotherpharmaceutically acceptable filler.

Preferred binders include cellulosic water soluble polymers such asmethylcellulose, starch, hydroxypropyl cellulose, gelatin,polyvinylpyrrolidone, polyethylene glycol, and/or anotherpharmaceutically acceptable binder.

Suitable processing aids include pharmaceutically acceptable processingaids for improving the flowability of the core materials duringprocessing. Preferred processing aids include, but are not limited to,colloidal silicon dioxide, talc, magnesium stearate, stearin, and/oranother pharmaceutically acceptable processing aid.

Preferred disintegrants include, but are not limited to, croscarmellosesodium, polyvinylpyrrolidone (crospovidone) sodium starch glycolate,and/or another pharmaceutically acceptable disintegrants.

We note, here, that using a disintegrant is particularly useful for theformulations in which L-menthol and the solubilizing oil are dispersedin the MCC-based gel. This is because the core may not release L-mentholfast enough for optimal treatment of some gastrointestinal disorders,such as FD (classified as a gastro-duodenal disorder) which requirerelease in the duodenum, or Crohn's disease which requires release inthe ileum or ulcerative colitis (classified as a colonic disorder) whichrequire release in the colon. Adding a disintegrant speeds up therelease of L-menthol from the core when the core reaches the desiredarea of the intestines.

The core may also include other active ingredients that behavesynergistically with L-menthol to treat gastrointestinal disorders.These other active ingredients include drugs typically used to treatvarious gastrointestinal issues including proton pump inhibitors (forFD), anti-inflammatories (for IBD), and immune suppressors (IBD).Combining L-menthol with these other active ingredients improves theirefficacy because of synergies in pharmacological activity and becauseL-menthol enhances their permeation into the intestinal walls.

Examples of PPIs include, but are not limited to omeprazole,lansoprazole, dexlansoprazole, esomeprazole, pantoprazole, rabeprazole,and ilaprazole. Including a PPI is preferred when the L-menthol in thecore is dissolved in caraway oil.

Examples of anti-inflammatory drugs include aminosalicylates, including5-aminosalicylate (5-ASA). Examples of 5-ASA are sulfasalazine,mesalamine, olsalazine and balsalazide. These work by decreasing theinflammation at the level of the lining of the gastrointestinal tract.However they do not address the pain and other symptoms associated withulcerative colitis or Crohn's disease. The 5-ASAs are poorly absorbed.They are more effective when they are released and locally delivered tothe ileum (for Crohn's disease) or colon (for ulcerative colitis). TheL-menthol in combination with aminosalicylates (in the core) and with anenteric coat specific for delivery at the appropriate pH between pH 6.8and 7.5 is useful for treating gastrointestinal disorders. We expectthis combination to be synergistic in addressing the needs of thepatients with the above disorders. Enteric coatings suited to thesePPI-containing formulations include hypromellose acetate succinatecoatings such as AQOAT AS-HF, AQOAT AS-HG, and poly(meth)acrylate-basedcoatings such as EUDRAGIT FS 30D or EUDRAGIT S-100).

Examples of immune suppressors include corticosteroids such asbudesonide, prednisone, prednisolone and methylprednisolone.Corticosteroids non-specifically suppress the immune response. Thesedrugs have significant short- and long-term side effects. They need tobe delivered to the ileum (for Crohn's disease) or colon (for ulcerativecolitis) for maximum efficacy. A combination of L-menthol withbudesonide, prednisone, prednisolone or methylprednisolone, formulatedin the core, with an enteric coat specific for delivery at theappropriate pH between pH 6.8 and 7.5 is useful for treatinggastrointestinal disorders, such as ulcerative colitis or Crohn'sdisease. This synergistic activity may allow the patient to receive alower dose of the corticosteroid in combination with L-menthol ascompared to the corticosteroid by itself. The unique activities ofL-menthol help relieve abdominal pain, cramps, and diarrhea. Entericcoatings suitable for these immune suppressor-containing formulationsinclude AQOAT AS-HF, AQOAT AS-HG, EUDRAGIT FS 30D or EUDRAGIT S-100.

In a particular embodiment of the multiparticulate formulation, theenteric coated cores comprise about 10% w/w to about 35% w/w ofL-menthol, about 40% w/w to about 75% w/w microcrystalline cellulose,and about 2% w/w to about 10% w/w methyl cellulose, and about 0.05% w/wto about 20% w/w of croscarmellose sodium; the subcoating comprisesabout 3.5% w/w to about 35% w/w of the uncoated cores; and the entericcoating comprises about 2% to about 35% w/w of the uncoated cores. Here,the % w/w refers to the % w/w/of the uncoated cores.

Because it is often desirable to be able to ship products innon-refrigerated vehicles and store them for a long period of time, wepreferred for our L-menthol-containing multiparticulate formulation tobe stable when stored at 40 degrees C. and 75% relative humidity, frombetween 1 day to 30 days, and even longer. This would also be useful ifthe multiparticulate composition is distributed in hotter regions suchas climate zone IV regions.

While developing multiparticulate compositions containing terpene-basedactive ingredients, we found that volatile ingredients sometimespenetrated the conventional subcoating materials we used to separate thecores form their enteric coatings. Because of this, the activeingredients would come in contact with the enteric coating if thetemperature was elevated (25 degrees C.-50 degrees C.) or thecomposition was stored for a long period of time. This somewhat reducedthe effectiveness of the enteric coating and amount of active ingredientin the core.

We solved this problem by developing a new subcoating material that maybe applied to the finished core and prevents volatile active ingredientsin the core from leaving the core and permeating the enteric coating atelevated temperatures. The subcoating includes a proteinaceous materialthat is applied along each core's exterior surface to form asubstantially continuous thin film that forms a barrier between the coreand the enteric coating that is applied after the subcoating.

Examples of proteinaceous materials that may be used in the subcoatinginclude proteins such as, but not limited to casein, whey protein, soyprotein, and various types of gelatin (Type A, Type B or derivatives ofgelatin) or proteinaceous materials that have protein-like structures. Aparticularly preferred material used to form the subcoating is asolution containing at least about 50% of the proteinaceous materialdispersed in a solvent. The solvent is preferably, but not necessarilywater. A particularly preferred proteinaceous material is Type Agelatin.

The proteinaceous subcoating is preferably applied to the core in liquidform and subsequently dried on the core. When dry, the subcoatingadheres to the core. Examples of the liquid form of the proteinaceoussubcoating material include melts and gels. When dry, the subcoatingforms a continuous film over the core and provides a barrier between thecore and enteric coating.

Gelatin typically melts at about 35 degrees C., which is below thenormal human body temperature of about 37 degrees C. Given this, onemight expect that, if a multiparticulate composition, including agelatin subcoating, is heated above 35 degrees C., the subcoating willmelt and release the active ingredients from the core. We observed,however, that gelatin subcoated multiparticulate compositions did notrelease the terpene-based active ingredients from the core even whenheated above 35 degrees C. This is a particularly unexpected result thatprovides numerous advantages.

Because the proteinaceous subcoating prevents volatile ingredients frombeing released from the core even when heating above the melting pointof the proteinaceous material, by applying the proteinaceous subcoating,one does not have to avoid heating the subcoated cores duringprocessing. One scenario in which this is advantageous is when theenteric coating is applied. Enteric coating polymers have a glasstransition temperature (T_(g)) that is often above 35 degrees C. Afterbeing applied to a core, enteric coated particulates are preferablyheated above T_(g) so that the enteric coating polymer can cure, therebyachieving optimum enteric protection of the core. Thus, using theproteinaceous subcoating between the core and enteric coating allows oneto achieve optimum enteric protection without releasing the L-mentholfrom the core.

The subcoating may be applied to the core as a gelatin-containingsubcoating solution. The solvent may be any solvent in which gelatin issoluble, such as water. In a preferred embodiment, the subcoatingsolution comprises about 5% to about 30% w/w gelatin and about 70% toabout 95% solvent. When the subcoating solution is allowed to dry aroundthe core, the solvent evaporates, leaving a thin gelatin film thatadheres to the core and forms a barrier between the core and entericcoating. The gelatin film subcoating is preferably about 3.5% w/w toabout 35% w/w of the enteric coated particulates. Surprisingly, in ourexperiments, drying cores containing peppermint oil and water, at about15 degrees C. to about 25 degrees C. did not result in significant lossof the L-menthol as the water was being removed by fluid bed drying.

The enteric coating is applied over each core, or, if a subcoating isused, over the subcoating. In a preferred embodiment, the entericcoating is about 2% w/w to about 35% w/w of the enteric coatedparticulate. A preferred enteric coating material is a methacrylic acidbased material such as a methacrylic acid based co-polymer. Thesematerials may be combined with other materials such as plasticizers forforming an enteric coating solution. In a typical embodiment, theenteric coating solution comprises about 5% w/w to about 35% w/w water,and the enteric-coated dried multiparticulates contain 0.5% w/w to about5% w/w plasticizer, about 0.05% w/w to about 5% w/w anti-adherent, andabout 2% w/w to about 35% w/w methacrylic acid copolymer. By way ofexample only, a suitable plasticizer is triethyl citrate and a suitableanti-adherent is PLASACRYL T20 (Emerson Resources, Inc., Norristown,Pa.). PLASACRYL T20 is an emulsion of anti-tacking agent and plasticizerand contains water, glyceryl monostearate, triethyl citrate andpolysorbate 80. The enteric coating is preferably about 3.5% w/w toabout 35% w/w of the enteric coated particulates.

The enteric coating material is selected to allow the L-menthol to bereleased in a preferred section of the intestines. By way of example,for the L-menthol to release in the colon, a sodium aliginate/ethylcellulose enteric coating may be used or an alternative enteric coatingmaterial that dissolves at close to pH 7.0.

If the proteinaceous subcoating is not used, it is preferred that theenteric coating material be applied to the core without heating the coreabove about 30 degrees C. so that the L-menthol does not degrade orvolatalize. This can be particularly difficult considering that entericcoatings are typically applied in a fluidized bed coater at sufficientair inlet temperature to result in a product temperature of about 38-42degrees C. Unfortunately, at such a high temperature, L-menthol tends todegrade and volatilize. This made it very difficult to produce a highpurity, solid L-menthol formulation that met or approximated the desiredUSP 711 enteric specifications. We found that both EUDRAGIT L30D-55 andKOLLICOAT MAE 30 DP were suitable because they could be reliably appliedto the cores at lower temperatures with good coalescence between theenteric coating and the underlying material. KOLLICOAT MAE 30 DP is amethacrylic acid-ethyl acrylate co-polymer. Without intending to bebound by theory, this may be because the glass transition temperatureT_(g) of these methacrylic acid based copolymers is roughly about 26° C.and depends on the plasticizer used. These methacrylic acid copolymerbased enteric coating materials do not require pH sensitive pore formersto dissolve at or near neutral pH.

The enteric-coated particulates may be coated with a finish coat. Thefinish coat is used, for example, to overcome the mucoadhesiveproperties of some enteric coating materials, which make themultiparticulates stick together during processing, storage, ordispensing through a tube for enteral feeding. The finish coat ispreferably a cellulosic derivative such as HPMC (hydroxylpropylmethylcellulose), HPC (hydroxyl propyl cellulose), CMC (carboxymethylcellulose), or another pharmaceutically acceptable finish coatingmaterial. When used, the finish coat is preferably about 1% to 10% w/wof the finished multiparticulate.

A particularly preferred finish coat material is HPMC because is notmucoadhesive. As such, it prevents the multiparticulates from stickingto the stomach wall as well as food in the stomach. This allows themultiparticulates to reach the intestines quickly, making the onset ofaction more reliable than the single-unit capsules.

The release profile of L-menthol in the body can be varied to treatdifferent disorders. L-menthol can be used to treat a plethora ofgastrointestinal disorders such as irritable bowel syndrome,inflammatory bowel disease (ulcerative colitis and Crohn's disease),gastroparesis, and functional dyspepsia, but it is best to release theactive ingredients at a certain point in the gastrointestinal tract tooptimally treat each disorder.

To treat gastrointestinal disorders associated with irritable bowelsyndrome, the multiparticulate composition is formulated to minimize theamount of L-menthol released into the stomach and colon, so that most ofit is released in the small intestine. Preferably, 20% or less of theL-menthol is released into the stomach and 20% or less of the L-mentholis released into the colon. Also, in many instances such as IBS, theL-menthol is preferably gradually released from the cores over about 4to about 6 hours after the cores pass the pyloric sphincter into thesmall intestine in order to deliver the active ingredients locally inthe small intestine. This release profile treats gastrointestinaldisorders by stabilizing the digestive system and alleviating thesymptoms associated with disorders such as irritable bowel syndrome.

To treat a gastrointestinal disorder such as functional dyspepsia(classified as a gastro-duodenal disorder), the multiparticulatecomposition is formulated so that the L-menthol or peppermint oil,dissolved in caraway oil, is rapidly released after themultiparticulates pass through the stomach and the pylorus, over thecourse of about 0 to about 2 hours in order to deliver L-menthol orpeppermint oil plus caraway oil locally to the duodenum section of thesmall intestine to help stabilize the digestive system and/or alleviatethe symptoms associated with functional dyspepsia.

Functional dyspepsia is recognized as a gastro-duodenal disorder(category B) according to the Rome III classification system.Preferably, 20% or less of the L-menthol or peppermint oil plus carawayoil is released in the stomach and 20% or less of the peppermint oil isreleased in the jejunum and ileum sections of the small intestine (whichfollow the duodenum) and the colon.

To treat a gastrointestinal disorder such as inflammatory bowel disease(including ulcerative colitis or Crohn's disease), the multiparticulatecomposition is formulated so that the L-menthol is rapidly releasedafter the multiparticulates pass through the stomach and the first 2sections of the small intestine (i.e. duodenum and jejunum, over thecourse of about 4 to about 6 hours, in order to deliver the L-menthollocally to the ileum or colon to attenuate the inflammatory responseand/or alleviate the symptoms associated with inflammatory boweldisease. Preferably, 30% or less of the oil-menthol is released in thestomach and the first 2 sections of the small intestine and greater than70% of the peppermint oil is released in the first 2 hours after themultiparticulates reach the pH of the ileum or colon.

In a particularly preferred embodiment, the enteric coated cores of themultiparticulate composition release at least about 35% of the L-mentholwithin about two hours, and at least about 80% of the L-menthol withinabout eight hours after being placed in an environment having a pH of 5to 8.

It should be understood that where this disclosure makes reference totreating a gastrointestinal disorder, that the terms “treat,” “treating,or any other variation of the word “treat,” includes prevention ormanagement of the gastrointestinal disorder. When MCC is used as arelease-controlling polymer, the core formulation allows one to achievea suitable release profile. One skilled in the art will recognize thatthat the release rate of L-menthol from the core can be adjusted byincluding a disintegrant, that actually functions as a disintegrant, oranother conventional release controlling polymer.

A daily dose of a multiparticulate composition containing L-menthol isabout 20 mg to about 1200 mgs of L-menthol, split into two or threedoses per day. Each dosage form may contain between 10 mgs and 140 mgsof L-menthol, more preferably, about 90-110 mg of L-menthol.

Doses of the multiparticulate composition may be administeredsporadically when needed for treating acute disruptions of thegastrointestinal tract or may be administered as part of a long termregimen for treating GI disorders such as irritable bowel syndrome,functional dyspepsia, gastroparesis, or inflammatory bowel disease. Atreatment subject may be a human or animal.

The enteric coated multiparticulates may be prepared into a suitablepharmaceutical or medical food dosage form such as a capsule, tablet orsachet, or are mixed with an acidic food vehicle and directly fedthrough a feeding tube. A typical dosage form contains about 400 mg ofthe particulates, but, depending on the desired dosage, this amount maybe adjusted. Acidic food vehicles include juices and foods such as, forexample, apple sauce and apple juice.

The multiparticulate formulation is preferably formulated to beadministered enterally, such as orally or through a feeding tube, to ahuman or animal subject to ensure that the subject receives an effectiveamount of L-menthol or peppermint oil over the course of several hoursafter ingestion. The feeding tube may help with subjects that haveachalasia, dysphagia, or another disorder that does not allow them toadminister a capsule orally with water. Alternatively themultiparticulates can be sprinkled onto apple sauce for patients thatcannot swallow larger sized capsules.

A preferred method of making the multiparticulate formulation is nowdescribed. The core is typically prepared by wet granulating the corematerials into a wet mass, extruding the wet mass to form an extrudate,breaking the extrudate into a plurality of core pieces, and spheronizingthe core pieces. The spheronized core pieces are then dried in a dryersuch as a fluid bed dryer to remove the water. If desired the driedspheronized cores are then sieved to separate cores of different sizes.

The dried spheronized cores are then coated with the proteinaceoussubcoating material if desired. One way to apply the subcoating materialto the cores is to prepare a subcoating solution and spray thesubcoating solution onto the cores. There are various conventionalmethods for doing this, but the preferred method is Wurster coating orfluid bed coating (top spray or bottom spray). The subcoating solutionis subsequently allowed to dry over the cores, leaving each core coatedwith a thin, continuous proteinaceous film. If desired, the subcoatedcores are sieved to separate them into different sizes.

The enteric coating is then applied to the subcoated cores or directlyto the cores if no subcoating is used. One means of applying the entericcoating is to spray it onto the subcoated cores. There are variousconventional methods for doing this, but the preferred method is Wurstercoating or fluid bed coating. The enteric coated particulates aresubsequently dried. During the enteric coating process, the cores arepreferably heated in an environment that is about 20 degrees C. to about50 degrees C. to cure the enteric coating materials above their T_(g).

A finish coating may be applied over the enteric coated particulates ifdesired. One way to apply the finish coating is to spray it onto theenteric coated cores. There are various conventional methods for doingthis, but the preferred method is Wurster coating or fluid bed coating.

A more particular method of making the multiparticulate formulationinvolves blending L-menthol from an at least 80% pure L-menthol sourcedissolved in an oil, microcrystalline cellulose, cellulose hydrophilicbinder, croscarmellose sodium and water to form a wet mass; extrudingthe wet mass to form an extrudate; dividing the extrudate intoindividual wet cores; drying the wet cores to form dried cores; andapplying an enteric coating to the dried cores.

Another method aspect of the invention is a method of treating agastrointestinal disorder in a subject. The method involvesadministering to the subject, a multiparticulate formulation comprisinga plurality of individual enteric coated containing L-menthol from an atleast 80% pure L-menthol source, the enteric coated cores beingeffective to release at least about 35% of the L-menthol within abouttwo hours, and at least about 80% of the L-menthol within about eighthours after being placed in an environment having a pH of 5 to 8. Themultiparticulate composition can be enterally administered through useof a conventional oral dosage form such as a tablet, caplet, capsule,sachet, or multiparticulate administered through a feeding tube, amongothers. The term “subject” includes human and animal subjects.

Another enteral means for administering the multiparticulate compositionorally is by adding it to food. In this instance, the multiparticulatecomposition is blended with an acidic food vehicle such as apple sauceor apple juice or another acidic vehicle that prevents premature releaseof the active ingredients and is then ingested by the subject.

The L-menthol-containing multiparticulate formulations may be used asmedical foods for the dietary management of various gastrointestinaldisorders or as medicaments.

Some of the multiparticulate formulations are geared to treat certaingastrointestinal disorders. When the enteric coated cores includeL-menthol dissolved in caraway oil (with or without a PPI), theformulation is suited to treat functional dyspepsia. When the entericcoated cores include L-menthol dissolved in peppermint oil, theformulation is suited to treat irritable bowel syndrome. When theenteric coated cores include L-menthol and one or more of green teaextract enriched with epigallocatechin gallate, aminosalicylate, orcorticosteroid, the formulation is suited to treat inflammatory boweldisease, including ulcerative colitis and Crohn's disease.

EXAMPLES

This section provides specific examples of the multiparticulatecomposition and method aspects of the invention. These examples areprovided to illuminate certain preferred aspects and embodiments of theinvention, but the scope of the invention is not limited to what theseexamples teach.

Example 1: Preparation of a Multiparticulate Formulation

The core was prepared using microcrystalline cellulose (MCC)commercially available under the name AVICEL® PH 102 (FMC Corp.,Philadelphia, Pa.), methylcellulose commercially available under thename METHOCEL® A15LV (Dow Chemical Co., Midland, Mich.), L-menthol, andUSP purified water.

33.25 kg MCC, 1.75 kg methylcellulose, and 15 kg L-menthol were blendedwith water to form a wet mass. The wet mass was granulated in a highshear granulator. The granulated wet mass was then extruded andspheronized. The spheronized particles were subsequently dried in afluid bed dryer to form uncoated cores. The drying temperature was about16 degrees C. to 20 degrees C.

The uncoated cores were Wurster coated with 37 kg of a subcoatingcomposition containing about 15% acid bone gelatin and 85% USP water anddried.

The subcoated cores were Wurster coated with 31 kg of a 20% w/w entericcoating suspension containing KOLLICOAT® MAE 30 DP, PLASACRYL T20,triethyl citrate USP, and purified water USP. The dry solids weight ofamount KOLLICOAT® MAE 30 DP was approximately 5.4 kg. The dry solidsweight of triethyl citrate was approximately 0.28 kg. The dry solidsweight of PLASACRYL T20 was approximately 0.5 kg. The enteric coatedcores were then dried at about 40 degrees C.

The enteric coated cores were Wurster coated with 26 kg of a finish coatsolution containing about 10% w/w hydroxyl propyl methyl cellulose and90% water USP and dried at about 40 degrees C.

Example 2: Stability Testing of the Multiparticulate Formulation ofExample 1

The multiparticulate composition described in Example 1 was subsequentlytested to ensure that the gelatin subcoating prevented the L-mentholfrom evaporating and leaving the core when stored at elevatedtemperatures over a long period of time.

In the first set of experiments, we prepared capsules containing themultiparticulate composition and stored them at 40 degrees C. and 75%relative humidity for four weeks. Each week, we measured the amount ofL-menthol in a selection of the capsules. FIG. 1 shows the results ofthis study as a graph of the number of milligrams of L-menthol percapsule as a function of time. The results show that the amount ofL-menthol in the capsules remained more or less constant at about 34 mgduring the four week period. This proves that the gelatin subcoatingmaintains the integrity of the core.

In the second set of experiments, we simulated the gastrointestinalenvironment and measured the dissolution profile of the multiparticulatecomposition to ensure that the enteric coating worked and that almostall of the L-menthol would be released from the core within about 8.5hours. This was a conventional two stage dissolution study in which thesample was placed in an acidic medium (0.1 N HCl) for about two hoursand subsequently placed in a neutral medium (pH=6.8) for the remainderof the time.

The results of this experiment are shown in FIG. 2 as the % release ofmgs of L-menthol over time. After two hours in the acidic medium, eachof the samples tested had only released about 10% or less of theL-menthol, indicating that the enteric coating was intact and workednormally. Over the following 6.5 hours in the neutral medium, theL-menthol was gradually released from the core.

Example 3: Preparation of a Multiparticulate Formulation

This prospective example illustrates a method for making an L-mentholmultiparticulate formulation, including a proteinaceous subcoating.

The core is made by blending 13 kg of solid L-menthol with 10 kg ofcaraway oil until the L-menthol dissolves. The L-menthol/caraway oilblend is mixed with 50 kg MCC, 2.7 kg methyl cellulose, and 7.5 kgcroscarmellose sodium. 38.8 kg of water is added to the mixture to formthe wet mass.

The wet mass is granulated in a high shear granulator. The granulatedwet mass was then extruded and spheronized. The spheronized particlesare subsequently dried in a fluid bed dryer to form uncoated cores. Thedrying temperature is about 16 degrees C.

The uncoated cores are Wurster coated with 203 kg of a subcoatingcomposition containing about 15% acid bone gelatin and 85% USP water anddried.

The subcoated cores are Wurster coated with 56 kg of a 20% w/w entericcoating suspension containing KOLLICOAT® MAE 30 DP, PLASACRYL T20,triethyl citrate USP, and purified water USP. The dry solids weight ofamount KOLLICOAT® MAE 30 DP is approximately 8.24 kg. The dry solidsweight of triethyl citrate is approximately 2.13 kg. The dry solidsweight of PLASACRYL T20 is approximately 0.82 kg. The enteric coatedcores are then dried at about 40 degrees C.

The enteric coated cores are Wurster coated with 36.9 kg of a finishcoat solution containing about 10% w/w hydroxylpropyl methyl celluloseand 90% water USP and dried at about 40 degrees C.

Unless otherwise defined, all technical and scientific terms used hereinare intended to have the same meaning as commonly understood in the artto which this invention pertains and at the time of its filing. Althoughvarious methods and materials similar or equivalent to those describedherein can be used in the practice or testing of the present invention,suitable methods and materials are described. The skilled shouldunderstand that the methods and materials used and described areexamples and may not be the only ones suitable for use in the invention.

The specification discloses typical preferred embodiments of theinvention, and although specific terms are employed, the terms are usedin a descriptive sense only and not for purposes of limitation. Theinvention has been described in some detail, but it will be apparentthat various modifications and changes can be made within the spirit andscope of the invention as described in the foregoing specification andin the claims.

That which is claimed is:
 1. A pharmaceutical dosage form comprising aneffective amount of L-menthol for treating a gastrointestinal disorder,the L-menthol being within a plurality of particulates having: (a) acore including crystalline L-menthol dissolved in a terpene-basedessential oil; and (b) a proteinaceous coating of a continuous film ofproteinaceous material over the core, forming a proteinaceous materialcoated core.
 2. The pharmaceutical dosage form of claim 1, wherein theplurality of particulates are in a capsule or packet-type dosage formfor oral delivery.
 3. The pharmaceutical dosage form of claim 1, whereinthe effective amount is about 10 mg to about 200 mg of L-menthol.
 4. Thepharmaceutical dosage form of claim 1, wherein the terpene-basedessential oil is peppermint oil.
 5. The pharmaceutical dosage form ofclaim 1, wherein the terpene-based essential oil is caraway oil.
 6. Thepharmaceutical dosage form of claim 1, wherein the proteinaceousmaterial includes gelatin.
 7. The pharmaceutical dosage form of claim 1,wherein the proteinaceous material includes acid bone gelatin.
 8. Thepharmaceutical dosage form of claim 1, wherein the proteinaceous coatingis a gelatin film.
 9. The pharmaceutical dosage form of claim 1, whereinthe particulates also have an enteric coating over the proteinaceousmaterial coated core.
 10. The pharmaceutical dosage form of claim 1,wherein the core also includes both of methylcellulose andmicrocrystalline cellulose.
 11. The pharmaceutical dosage form of claim1, wherein: the terpene-based essential oil is peppermint oil; theproteinaceous coating is a continuous coating of gelatin; and amethacrylic acid based polymer coating is over the proteinaceousmaterial coated core.
 12. The pharmaceutical dosage form of claim 1,wherein: the terpene-based essential oil is caraway oil; theproteinaceous coating is a continuous coating of gelatin; and amethacrylic acid based polymer coating is over the proteinaceousmaterial coated core.
 13. The pharmaceutical dosage form of claim 1,wherein the proteinaceous coating is effective to substantially preventL-menthol in the core from leaving the core when stored at a temperatureof 40 degrees C. and 75% relative humidity for between 1 day to 30 days.